Increasing evidence suggest that green tea is a potent inhibitor of chemical carcinogenesis in rodents. The reported mechanisms for chemopreventive activity of green tea are antioxidation, induction of Phase II enzymes, inhibition of TNFalpha expression and release, inhibition of celt proliferation, and induction of apoptosis. Among these, cell cycle arrest and apoptosis induced by green tea are probably the most significant factors. However, the exact mechanism for the action of green tea on apoptosis and cell cycle arrest is not clear at present. The overall objective of this proposal is to characterize green tea preclinically as a potent lung cancer chemopreventive agent and to determine the molecular mechanism that underlie the efficacy of green tea in preventing lung cancer in mice. Previously, we and others have reported inhibition of lung tumor development using both A/J mice and p53 transgenic mice. We hypothesize that green tea will prevent chemically induced lung adenocarcinoma formation in a mutant mouse model with genetic changes commonly seen in human lung cancers, and the chemopreventive effect of green tea is, in part, mediated by AP-1, NFkappaB, or E2F1. Specific aims include: 1. To evaluate the effect of green tea on lung adenocarcinoma carcinogenesis in a transgenic mouse lung carcinoma model with genetic changes commonly seen in human lung cancers; 2. To evaluate chemopreventive effect of green tea against lung cancer by exposing mice to aerosolized EGCG in mutant mouse lung carcinoma model; 3. To examine the effect of green tea on cell cycle regulation and apoptotic activity of mouse lung tumors in vivo and lung tumor cell lines in vitro; 4. To investigate the mechanism of green tea's chemopreventive efficacy against lung cancer in mice. This proposal is timely and significant for the following reasons. Firstly, our proposed chemoprevention clinical trial of green tea against lung cancer in humans requires vigorous preclinical characterization of its efficacy and mechanism(s). Secondly, we will use a newly developed mutant mouse lung tumor model, which shares both histopathological features and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung adenocarcinogenesis. And thirdly, we will conduct comprehensive animal bioassays to test the efficacy of green tea that is delivered via aerosol to significantly increase the efficacy of green tea in preventing lung cancer. The results from this proposal will providc a solid foundation for clinical trials of green tea as a lung cancer chemopreventive agent. Furthermore, the results from this proposal will also provide significant insights on how green tea affect the genes associated with cell cycle regulation and apoptosis during mouse lung carcinogenesis process.